The object of this proposal is to analyze in depth the expression of regulatory phenotypes of normal and leukemic human progenitor cells, to correlate regulatory phenotype with the growth behavior of progenitor cells in vitro, and to define mechanisms for altering abnormal phenotypes in order to modify abnormal cell differentiation. The effects of prostaglandin E, PGE, on granulocyte-macrophage committed progenitor cell, CFU-GM, cell cycle and their association with the control of normal and leukemic cell proliferation will be analyzed in primary soft agar and continuous long term bone marrow culture. A unique limited suspension culture system will be used to modulate CFU-GM HLA-DR expression and investigate its implication in the control of CFU-GM proliferation and its application to the control of disordered regulation observed in patients wiyh leukemia. A multi-faceted in-depth study of specific modulation of antigenic expression and regulatory responsiveness in a strategy designed to restore a normal pattern of proliferation and differentiation offers a mechanism for control of leukemic cell proliferation and suggests an alternative approach to therapy . The mechanism of action and specificty of PGE will be studied, both in suspension and semi-solid matrix culture, using agents which mimic the action of; inhibit the biosynthesis of; interfere with the binding of; or modify cellular sensitivity to, PGE. Biophysical and immunological cell separatory procedures will be used to analyze normal and leukemic responder and accessory cell populations. Clone transfer and recloning capacity will be used to investigate the effects of prostaglandin and other host response modifiers on normal and leukemic stem cell differentiation, committment and self renewal. Leukemic cell lines will be used as models for studying modulation of differentiation and regulatory control. The effects of PGE on murine granulocyte-macrophage production, CFU-GM cell cycle, differentiation, Ia-antigen expression and response to growth regulation will be determined in vivo using two intact animal models and the stable 16,16-dimethyl PGE2 analog. The ability of prostaglandin and other response modifiers to alter the hematopoietic regulatory capacity of monocytes and macrophages will be determined.